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Aripiprazole increases NAD(P)H–quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells

  • Translational Neurosciences - Original Article
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Abstract

We previously showed that aripiprazole increases intracellular NADPH and glucose-6-phosphate dehydrogenase mRNA in PC12 cells. Aripiprazole presumably activates a system that concurrently detoxifies reactive oxygen species and replenishes NADPH. Nrf2, a master transcriptional regulator of redox homeostasis genes, also activates the pentose phosphate pathway, including NADPH production. Therefore, our aim was to determine whether aripiprazole activates Nrf2 in PC12 cells. Aripiprazole increased mRNA expression of Nrf2-dependent genes (NAD(P)H–quinone oxidoreductase-1, Nqo1; heme oxygenase-1, HO1; and glutamate-cysteine ligase catalytic subunit) and protein expression of Nqo1 and HO1 in these cells (p < 0.05). To maintain increased Nrf2 activity, it is necessary to inhibit Nrf2 degradation; this is done by causing Nrf2 to dissociate from Keap1 or β-TrCP. However, in aripiprazole-treated cells, the relative amount of Nrf2 anchored to Keap1 or β-TrCP was unaffected and Nrf2 in the nuclear fraction decreased (p < 0.05). Aripiprazole did not affect phosphorylation of Nrf2 at Ser40 and decreased the relative amount of acetylated Nrf2 (p < 0.05). The increase in Nqo1 and HO1 in aripiprazole-treated cells cannot be explained by the canonical Nrf2-degrading pathways. Further experiments are needed to determine the biochemical mechanisms underlying the aripiprazole-induced increase in these enzymes.

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Abbreviations

β-TrCP:

β-Transducin repeat-containing protein

DMEM:

Dulbecco’s modified Eagle’s medium

G6PD:

Glucose-6-phosphate dehydrogenase

Gcl-C:

Glutamate-cysteine ligase catalytic subunit

Gcl-M:

Glutamate-cysteine ligase modifier subunit

GSK3β:

Glycogen synthase kinase 3β

Gstp1:

Glutathione S-transferase π1

HO1:

Heme oxygenase-1

HPRT:

Hypoxanthine–guanine phosphoribosyltransferase

HRP:

Horseradish peroxidase

Ig:

Immunoglobulin

Keap1:

Kelch-like ECH-associating protein 1

MTHFD2:

Methylenetetrahydrofolate dehydrogenase 2

Nqo1:

NAD(P)H−quinone oxidoreductase-1

Nrf2:

NF-E2 p45-related factor 2

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate-buffered saline

PI3K:

Phosphatidylinositide 3-kinase

PKC:

Protein kinase C

p-Akt (Ser473):

Akt phosphorylated at Ser473

p-Akt (Thr308):

Akt phosphorylated at Thr308

p-GSK3β (Ser9):

GSK3β phosphorylated at Ser9

p-Nrf2 (Ser40):

Nrf2 phosphorylated at Ser40

PPAT:

Phosphoribosyl pyrophosphate amidotransferase

ROS:

Reactive oxygen species

SDS:

Sodium dodecyl sulfate

Taldo:

Transaldolase

Tkt:

Transketolase

xc-system:

Anionic amino acid transporter light chain

xCT:

Xc-system member 11 (Slc7a11)

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Acknowledgments

This work was supported by grants-in-aid from Fujita Health University to AO and YSK and by grants-in-aid from Kinjo University to KM.

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Authors and Affiliations

  1. Department of Physiology, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Yoko S. Kaneko, Hiroshi Nagasaki, Yu Kodani, Akira Nakashima & Akira Ota

  2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Takeshi Takayanagi, Atsushi Suzuki & Mitsuyasu Itoh

  3. Department of Health Sciences, Kinjo University, Hakusan, 924-8511, Japan

    Keiji Mori

  4. Department of Pharmacology, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan

    Kazunao Kondo & Toshiharu Nagatsu

  5. Department of Psychiatry, Tosei General Hospital, Seto, 489-8642, Japan

    Miyuki Ota

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  1. Yoko S. Kaneko
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  2. Takeshi Takayanagi
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  3. Hiroshi Nagasaki
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  4. Yu Kodani
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  8. Mitsuyasu Itoh
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  9. Kazunao Kondo
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  10. Toshiharu Nagatsu
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  11. Miyuki Ota
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  12. Akira Ota
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Correspondence to Akira Ota.

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Y. S. Kaneko and T. Takayanagi contributed equally to this article.

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Kaneko, Y.S., Takayanagi, T., Nagasaki, H. et al. Aripiprazole increases NAD(P)H–quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells. J Neural Transm 122, 757–772 (2015). https://doi.org/10.1007/s00702-014-1350-8

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